Mucositis, the inflammation of mucosal tissue, is a serious medical problem that affects millions of people worldwide. In the respiratory tract, mucositis affects not only the nose, sinuses and the large airways but also the small airways of the lungs. Mucositis of the nasal cavity and/or paranasal sinuses is called rhinosinusitis. Rhinosinusitis is estimated to affect approximately 35 million Americans annually, and an estimated 90% of all rhinosinusitis cases are chronic (CRS). Of CRS sufferers, up to 500,000 people resort to sinus surgery each year.
CRS has been a confusing disease for medical providers due to a limited understanding of its pathophysiology and its limited treatment options. Due to the small number of controlled studies examining medical treatments for CRS, there are currently no FDA-approved medical treatments. The lack of robust clinical and laboratory markers to assess the severity of CRS has further hampered efforts to evaluate the efficacy of treatment.
CRS results in a variety of symptoms, including nasal congestion, facial pain and pressure, nasal discharge, and headaches. Historically, the treatment of CRS has largely focused on addressing the symptoms of the condition through acute antibiotic therapy, intranasal or oral corticosteroids, and sinus surgery. While antibiotics are useful in treating the acute exacerbations that result from the bacterial invasion of the damaged paranasal tissue of CRS patients, no antibiotic has proven effective in eradicating the underlying cause of CRS. Intranasal and oral corticosteroids, which are potent anti-inflammatory hormones, have been used to reduce the inflammation that plays a role in CRS, but oral corticosteroids can cause serious side effects and must be avoided or cautiously used with patients that have certain conditions, such as gastrointestinal ulcers, renal disease, hypertension, diabetes, osteoporosis, thyroid disorders, and intestinal disease. Surgery is frequently used in CRS patients to improve the drainage of their sinuses based on the assumption that the disease can be reversed by identifying and correcting the obstruction that caused the condition, but while such surgery usually offers temporary relief of symptoms, it is typically not curative.
Efforts to establish treatments for CRS have been frustrated by the reported heterogeneity of the disease. A variety of causes have been suggested for CRS, including bacterial infection, viral infection, fungal allergy (allergic fungal sinusitis), fungal infection (invasive), ubiquitous fungi leading to an inappropriate immune response, humoral immunodeficiency, and allergic and nonallergic rhinitis. Several studies have contributed to the accumulating body of literature that examines the efficacy of antifungal treatments of CRS. Research into the pathophysiology of CRS led to the discovery that eosinophils appear to become activated in the presence of fungi, and that fungi were ubiquitous in nasal secretions in both CRS patients and healthy individuals (Ponikau J. U. et al., “The diagnosis and incidence of allergic funal sinusitis,” Mayo Clin. Proc., 74:877-884 (1999)). Furthermore, an aberrant Th2-like immune response to fungi was observed in peripheral blood mononuclear cells from patients with CRS compared to controls (Shin S. H. et al., “Chronic rhinosinusitis: an enhanced immune response ubiquitous airborne fungi,” J. Allergy Clin. Immunol., 114:369-1375 (2004)). This research formed the basis for the fungi-immunological response hypothesis, which remains controversial today, i.e., that elimination of fungi will attenuate the aberrant immune response involving IL-5 production, eosinophil accumulation and activation, and toxic effects from release of eosinophil mediators such as eosinophilic major basic protein (Rank, M. A. et al., “Antifungal therapy for chronic rhinosinusitis: the controversy persists,” Curr. Opin. Allergy Clin. Immunol., 9:67-72 (2009)). U.S. Pat. Nos. 6,555,566, 6,291,500 and 6,207,703, by Dr. Jens Ponikau and assigned to the Mayo Foundation For Medical Education And Research, describe and claim methods of treating non-invasive fungus-induced rhinosinusitis, asthma, or intestinal mucositis by directly mucoadministering to at least a portion of the nasal-paranasal anatomy of the subject a formulation including an antifungal agent in an amount, at a frequency, and for a duration effective to reduce or eliminate the non-invasive fungus-induced rhinosinusitis, asthma, or intestinal mucositis. The contents of these references are incorporated in their entireties by this reference.
Mucositis is also a dose-limiting side effect of cancer therapy and bone marrow transplantation (Sonis, “Oral Complications,” in: Cancer Medicine, pp. 2381-2388, Holand et al.; Eds., Lea and Febiger, Philadelphia (1993a); Sonis, “Oral Complications in Cancer Therapy,” In: Principles and Practice of Oncology, pp. 2385-2394, De Vitta et al., Eds., J. B. Lippincott, Philadelphia (1993b). Oral mucositis is found in almost 100% of patients receiving radiotherapy for head and neck tumors, in about 40% of patients receiving chemotherapy, and in about 90% of children with leukemia (Sonis, 1993b, supra). Complications related to oral mucositis, though varying in the different patient populations, generally include pain, poor oral intake with consequent dehydration and weight loss, and systemic infection with organisms originating in the oral cavity leading to septicemia (Sonis, 1993b; U.S. Pat. No. 6,025,326, by Steinberg et al., assigned to IntraBiotics Pharmaceuticals, Inc.; U.S. Pat. No. 6,946,118, by Lawter et al., assigned to Orapharma, Inc.), In addition to the oral cavity, mucositis may also affect other parts of the gastrointestinal tract. Various approaches to treating oral mucositis and associated oral infections have been investigated with limited success (Loprinzi et al., Sem. Oncol. 22 Suppl. 3): 95-97 (1995); Epstein & Wong, Int. J. Radiation Oncology Biol. Phys. 28:693-698 (1994); Verdi et al., Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 80:36-42 (1995)).
Despite the clear need for effective agents to treat and prevent mucositis, none of the current interventions provide significant long-term relief or significantly decrease the severity or duration of mucositis, particularly CRS. There is currently no curative treatment for mucositis.